Pharmaceutical dosage forms fabricated with nanomaterials for quality monitoring

ABSTRACT

Nanomaterials fabricated to pharmaceutical dosage forms used to monitor quality of the drug product enclosed therein are disclosed. The nanomaterials are useful to provide a plurality of quality analysis to the dosage form. Consequently, the nanomaterials provide a means to perform quality testing on a continuous basis throughout the supply chain, including the cold chain whereby manufacturers and distributors can achieve greater product integrity and longer shelf life and ultimately minimize cost. The end user benefits in obtaining the highest quality drugs at the time of need.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNo. 60/937,924 filed 30 Jun. 2007, the contents of which are fullyincorporated by reference herein.

STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH

Not applicable.

FIELD OF THE INVENTION

The invention described herein relates to the field of pharmaceuticaldosage forms and nanotechnologies. Specifically, nanomaterials used forthe monitoring of quality in pharmaceutical dosage form technologies.The invention further relates to the enhancement of nanotechnologies toproduce higher quality more efficient drug storage forms whereby theshelf life of high quality drugs will increase.

BACKGROUND OF THE INVENTION

We endeavor to further the state of the art using nanomaterials in thefield of pharmaceutical dosage forms and formulation technology.

Nanotechnology is a field of applied science and technology covering abroad range of topics. The main unifying theme is the control of matteron a scale smaller than one micrometer as well as the fabrication ofdevices on this same length scale. Worldwide research is currently beingconducted in countless areas to discover new and useful areas wherenanotechnology can be exploited commercially. The research involvespotential utility in industrial applications, such as pharmaceuticalpackaging as well as other areas of medicine and bio-energy just to namea few.

Despite the apparent simplicity of this definition, nanotechnologyactually encompasses diverse lines of inquiry. Nanotechnology cutsacross many disciplines, including colloidal science, chemistry, appliedphysics, biology. It could variously be seen as an extension of existingsciences into the nanoscale, or as a recasting of existing sciencesusing a newer, more modern term.

Two main approaches are used in nanotechnology. One is a “bottom-up”approach where materials and devices are built from molecular componentswhich assemble themselves chemically using principles of molecularrecognition. The other being a “top-down” approach where nano-objectsare constructed from larger entities without atomic-level control.

Nanomaterials are materials having unique properties arising from theirnanoscale dimensions. The use of nanoscale materials can also be usedfor bulk applications. In fact, most present commercial applications ofnanotechnology are of this flavor.

Nanomaterials from a “top-down” design have certain scaling deficiencieswhich must be assessed. For example, A number of physical phenomenabecome noticeably pronounced as the size of the system decreases. Theseinclude statistical mechanical effects, as well as quantum mechanicaleffects, for example the “quantum size effect” where the electronicproperties of solids are altered with great reductions in particle size.This effect does not come into play by going from macro to microdimensions. However, it becomes dominant when the nanometer size rangeis reached. Additionally, a number of physical properties change whencompared to macroscopic systems. One example is the increase in surfacearea to volume of materials. This catalytic activity also openspotential risks in their interaction with biomaterials.

Additionally, materials reduced to the nanoscale can suddenly show verydifferent properties compared to what they exhibit on a macroscale,enabling unique applications. For instance, opaque substances becometransparent (copper); inert materials become catalysts (platinum);stable materials turn combustible (aluminum); solids turn into liquidsat room temperature (gold); insulators become conductors (silicon) toname a few.

Additionally, nanosize powder particles are important for theachievement of uniform nanoporosity and similar applications. However,the tendency of small particles to form clumps (“agglomerates”) is aserious technological problem that impedes such applications.

Another deficiency is that the volume of an object decreases as thethird power of its linear dimensions, but the surface area onlydecreases as its second power. This somewhat subtle and unavoidableprinciple has huge ramifications. For example the power of a drill (orany other machine) is proportional to the volume, while the friction ofthe drill's bearings and gears is proportional to their surface area.For a normal-sized drill, the power of the device is enough to handilyovercome any friction. However, scaling its length down by a factor of1000, for example, decreases its power by 1000³ (a factor of a billion)while reducing the friction by only 1000² (a factor of “only” amillion). Proportionally it has 1000 times less power per unit frictionthan the original drill. If the original friction-to-power ratio was,say, 1%, that implies the smaller drill will have 10 times as muchfriction as power. The drill is useless.

This is why, while super-miniature electronic integrated circuits can bemade to function, the same technology cannot be used to make functionalmechanical devices in miniature.

Nanomaterials from a “bottom-up” design also have certain deficiencieswhich must be assessed. Modern synthetic chemistry has reached the pointwhere it is possible to prepare small molecules to almost any structure.These methods are used today to produce a wide variety of usefulchemicals such as pharmaceuticals or commercial polymers. However, theability of this to extend into supramolecular assemblies consisting ofmany molecules arranged in a well defined manner is problematic. Suchbottom-up approaches should, broadly speaking, be able to producedevices in parallel and much cheaper than top-down methods. However,most useful structures require complex and thermodynamically unlikelyarrangements of atoms. The basic laws of probability and entropy make itvery unlikely that atoms will “self-assemble” in useful configurations,or can be easily and economically nudged to do so. About the onlyexample of this is a crystal growing, for which Nanotechnology cannottake any credit.

Given the deficiencies associated with “top-down” and “bottom-up”nanomaterials, it becomes clear that providing a functional approach tonanotechnology (i.e. the development of nanomaterials of a desiredfunctionality) can be problematic.

Finally, implementing nanotechnologies in highly-regulated bulkpackaging applications, such as pharmaceutical formulation and dosageforms, only compounds problems. The present invention overcomes theseproblems.

In relation to pharmaceutical dosage forms, soft gelatin capsules, nowmore commonly known as softgels, have been well known and widely usedfor many years. Softgels generally comprise an outer shell primarilymade of gelatin, a plasticizer, and water, and a fill contained withinthe shell. However, other materials as a substitute for gelatin can beused, such as gum acacia and other non-gelatin substitutes. The fill maybe selected from any of a wide variety of substances that are compatiblewith the shell. Softgels are widely used in the pharmaceutical industryas an oral dosage form containing many different types of pharmaceuticaland vitamin products. In addition to use as an oral dosage form fordrugs and vitamins, soft gelatin capsules or softgels are also designedfor use as suppositories for rectal or vaginal use. Other uses are fortopical and ophthalmic preparations and the like. The cosmetic industryalso uses softgels as a specialized package for various types ofperfumes, oils, shampoos, skin creams and the like. Softgels areavailable in a great variety of sizes and shapes, including roundshapes, oval shapes, oblong shapes, tube shapes and other special typesof shapes such as stars. The finished capsules or softgels can be madein a variety of colors. In addition, opacifiers may be added to theshell.

Although softgels can be made in a wide variety of shapes, sizes andcolors, because of the wide range of use of softgels, there is adefinite need to provide improved means of monitoring quality of thedosage form (i.e. capsule) and other means of identification. In thisregard, it is quite common today to have an indicia of some type printedon each softgel after formation. The printing material may be anysuitable dye or pigment. In some equipment, this has the disadvantage ofrequiring the use of an additional machine that will align the softgelsand hold them in a desired oriented position for the application of thedye or ink. The use of additional equipment and procedural steps adds tothe overall cost of manufacture of the softgels and, therefore, thissystem is considered disadvantageous. Also, the printing of each softgelcan be done over only a limited portion of the exterior surface of thesoftgel and may not be readily read or even seen by the consumer.Specific examples of known processes and machines used for applying sometype of identification on the softgels are those shown, for example, inPower (Posner) U.S. Pat. No. 2,449,139; Scherer U.S. Pat. No. 2,623,494;Scherer U.S. Pat. No. 2,688,775; Scherer U.S. Pat. No. 2,688,775; TaylorU.S. Pat. No. 3,124,840; Hansen U.S. Pat. No. 3,203,347; and VincentU.S. Pat. No. 3,333,031.

In the rotary die process for manufacturing softgels, two gelatinribbons are prepared, fed simultaneously to the fill area, andsimultaneously and continuously filled, formed, hermetically sealed, andautomatically cut between two rotary dies. The Scherer U.S. Pat. No.2,623,494 relates to a banding machine for softgels. In this machine,the identifying band is applied to each individual capsule after thecapsule is formed. The Scherer U.S. Pat. No. 2,688,775 shows a methodfor applying a brand to the exterior surface of a gelatin capsule. TheScherer U.S. Pat. No. 2,703,047 discloses a similar system of brandingthe filled capsules. In the Taylor U.S. Pat. No. 3,124,840, a printingelement is provided in order to print on the gelatin strip prior to theformation of the capsule. The Hansen U.S. Pat. No. 3,203,347 shows amarking fluid that is printed on the gelatin ribbon used to make thesoftgels. The Vincent U.S. Pat. No. 3,333,031 shows dying of the gelatinstrip before capsule formation. Even though efforts have been made tomanufacture gelatin capsule and distinguish them from those of others byusing different shapes, sizes, colors, color combinations, branding,banding, and printing, there still is a need to provide a way to evenmore uniquely identify whether the drug product within the dosage formis still viable while accomplishing this in a very unique, economical,and simplified manner.

In addition, growing demand for patient-friendly drug delivery forms hasalso increased interest in aseptic prefilled systems, such as pre-filledsyringes. Pre-filled dosage forms reduce the risk of misidentification,dosage error and contamination. Additionally, pre-filled dosage formseliminate container overfill that can be associated with vials. This isimportant when the product is in short supply, such as a vaccine.However, switching to a prefilled syringe presents its own set ofchallenges for manufacturers. In a prefilled syringe, a drug is exposedto materials it does not encounter in a vial. For example, lubricationis of limited importance in a stopper for a vial. In syringes, however,lubricity is essential to proper functioning of the device. The plungermust move smoothly and easily. Silicone is often used to ensurelubricity. Determining how silicone will interact with a given drug'sstability and aggregation is a problem for both formulators and fillers.The current invention addresses these problems.

Finally, the need for quality monitoring in supply chain management ofdosage forms is becoming increasingly important. Cold Chain refers to asubset of the total supply chain involving the production, storage, anddistribution of drug products that require some level of temperaturecontrol in order to retain the drugs key characteristics and properties.The most critical portion of cold chain management is the distributionphase of drugs to the end-user (i.e. patient). The Food and DrugAdministration requires that these drug products be stored underappropriate conditions so that their identity, strength, quality,effectiveness, and purity are not affected. However, many variablesaffect these properties, such as facility temperature deviation,airflow, air quality, duration of storage, container integrity, andseasonal considerations. Currently, quality is monitored on adestination-by-destination method.

The aforementioned background shows that a fundamental change is neededin the way quality is monitored for pharmaceutical formulations anddosage forms from the point of packaging until the time the drug reachesthe end user. The present invention addresses these problems.

SUMMARY OF THE INVENTION

The invention provides for nanomaterials with functional characteristicsthat can be interfaced with pharmaceutical dosage forms. Specifically,nanomaterials fabricated to dosage forms that monitor the quality of thedrug product enclosed therein. The nanomaterials can be designed tomonitor a plurality of properties including but not limited to pH,temperature, potency, phase transition, solubility, particle size,polymorphisms, leachates, or any property (chemical or physical) thateffects the activity or the drug product. As used herein, the term“drug” is synonymous with “pharmaceutical”. In certain embodiments, thenanomaterial is fabricated to an encapsulated dosage form and quality ismonitored to ensure purity and consistency of a pharmaceuticalformulation.

In one embodiment, the nanomaterial is fabricated to a pre-filledsyringe dosage form and quality is monitored to ensure potency of avaccine.

In a further embodiment, the nanomaterial is fabricated to a dosage formenclosing an emulsion and phase transition is monitored to ensure properefficacy at the time of use.

In a further embodiment, the nanomaterial is fabricated to a dosage formset forth in Table I.

The invention further comprises methods of fabricating a nanomaterialinto a dosage form.

The invention further comprises methods of fabricating a nanomaterialinto a dosage form set forth in Table I.

The invention further comprises methods of monitoring quality of a drugproduct enclosed within a dosage form fabricated with nanomaterials.

In a further embodiment, the invention provides for a method ofmonitoring quality of a drug product whereby the dosage form comprises ananomaterial fabricated into the dosage form and whereby the monitoringoccurs from packaging to distribution.

In a further embodiment, the invention provides for a method ofmonitoring quality of a drug product whereby the dosage form comprises ananomaterial fabricated into the dosage form and whereby the monitoringoccurs from distribution to wholesale.

In a further embodiment, the invention provides for a method ofmonitoring quality of a drug product whereby the dosage form comprises ananomaterial fabricated into the dosage form and whereby the monitoringoccurs from wholesale to retail.

In a further embodiment, the invention provides for a method ofmonitoring quality of a drug product whereby the dosage form comprises ananomaterial fabricated into the dosage form and whereby the monitoringoccurs from retail to the end user.

In a further embodiment, the invention provides for a method ofmonitoring quality of a drug product in a cold chain whereby the dosageform comprises a nanomaterial fabricated into the dosage form andwhereby the temperature monitoring occurs from packaging to the enduser.

In a further embodiment, the inventions comprises a dosage formfabricated with a nanomaterial whereby said dosage form encloses a drugproduct and whereby said nanomaterial monitors quality of said drugproduct.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. Nanomaterial with Thermal Conductivity Properties Fabricated inSheet Form. Nanomaterial is functionalized with the property of thermalconductivity. Organic matrix comprising polyhedral oligomericsilsesquioxane (“POSS”). Particle size is between the range of about 10nm and about 130 nm. Thermally conductive filler is used to reinforcenanomaterial. Nanomaterial is fabricated into a sheet with flat surfacewhereby the sheet interfaces a drug product and monitors the temperatureof the drug product via a thermal biosensor.

FIG. 2. Thermal Interface Pad Fabricated in a pre-Filled Syringe toMonitor Temperature of a Vaccine. The thermal pad is interfaced with thedrug product enclosed within the pre-filled syringe. The thermal pad isoperably linked to a thermal biosensor to monitor temperature of thevaccine. Thermal biosensor is pre-set to “Cool” (i.e. Between 8° and 15°C. (46° and 59° F.)). Identification schema alerts end user whentemperature is outside of pre-set condition.

FIG. 3. Monitoring and Detection Schema Using Nanomaterials withEnhanced Luminescence. Nanomaterials with enhanced luminescenceproperties are made using methods known in the art. The nanomaterial isfabricated into a dosage form to monitor quality of the drug productenclosed therein. A pre-determined schema will show when qualityparameters fall outside the scope of the pre-set parameters. The schemadisplays a wide variety of displays. FIG. 3A. Shows the schema ofchanging colors. FIG. 3B. Shows the schema of symbol display. FIG. 3C.Shows the schema of word display.

FIG. 4. Nanomaterials with Enhanced Optical Properties Fabricated withPharmaceutical Dosage Forms. Nanomaterial is functionalized withenhanced optical properties. A Graded Index Lens (“GRIN”) is fabricatedusing a polymer/nanocrystal blend using methods known in the art. TheGRIN lens has uniform thickness to provide for maximum interface withthe dosage form and the optical fiber. The contact sensor is fabricatedwith a pharmaceutical dosage form.

FIG. 5. Optical Contact Sensor Fabricated into Dosage Form to MonitorPhase Transition of Emulsion. Contact sensor is fabricated into a dosageform and monitors phase transition of an emulsion. Upon an event takinga pre-determined quality parameter outside the quality protocol anend-user visually identifies the phase transition as outside the qualityparameters.

FIG. 6. Schematic of Supply Chain Distribution in Drug Packaging. Oncefinal formulation is determined the drug product is packaged using thefabricated dosage forms described herein. The dosage forms travel frompackaging to distribution to wholesale to doctors or retail or hospitalsand then to the end-user. The fabricated dosage forms monitor pre-setquality parameters and if an event takes the quality parameters outsidethe scope of the pre-set parameters the end-user is notified by apre-set schema. Note, the supply chain can include several differentconfigurations.

DETAILED DESCRIPTION OF THE INVENTION

Outline of Sections

I.) Definitions

II.) Nanomaterial

-   -   a. Functional Properties of Nanomaterial        -   i. Nanomaterial with thermal Conductivity        -   ii. Nanomaterial with Porosity/Permeability        -   iii. Nanomaterial with enhanced luminescence        -   iv. Nanomaterial with enhanced acoustics        -   v. Nanomaterial with magnetic properties        -   vi. Nanomaterial with enhanced solubility        -   vii. Shape Engineered nanomaterials        -   viii. Nanomaterials with enhanced optical properties

III.) Sensors

IV.) Pharmaceutical Formulations

V.) Pharmaceutical Dosage Forms

VI.) Routes of Administration

VII.) Supply Chain Management

VIII.) KITS/Articles of Manufacture

I.) Definitions:

Unless otherwise defined, all terms of art, notations and otherscientific terms or terminology used herein are intended to have themeanings commonly understood by those of skill in the art to which thisinvention pertains unless the context clearly indicates otherwise. Insome cases, terms with commonly understood meanings are defined hereinfor clarity and/or for ready reference, and the inclusion of suchdefinitions herein should not necessarily be construed to represent asubstantial difference over what is generally understood in the art.Many of the techniques and procedures described or referenced herein arewell understood and commonly employed using conventional methodology bythose skilled in the art.

As used herein the terms “drug” and “pharmaceutical” include veterinarydrugs and human drugs, including human biological drug products.

“Nanomaterial” means a material in any dimensional form (zero, one, two,three) and domain size less than 100 nanometers.

“Nanostructure” means a structure having at least one dimension that isless than 500 nanometers. Examples, include but are not limited tonanocrystals, nanocomposites, nanograins, nanotubes, nanoceramics, andnanopowders.

“nanocrystal” means nanostructures that are substantiallymonocrystalline. A nanocrystal has at least one region or characteristicdimension with a dimension of less than about 500 nm, and down to on theorder of less than about 1 nm. As used herein, when referring to anynumerical value, “about” means a value of .+−.10% of the stated value(e.g. about 100 nm encompasses a range of sizes from 90 nm to 110 nm,inclusive). The terms “nanocrystal,” “nanodot,” “dot” and “quantum dot”are readily understood by the ordinarily skilled artisan to representlike structures and are used herein interchangeably. The presentinvention also encompasses the use of polycrystalline or amorphousnanocrystals.

“aspect ratio” means the ratio of the maximum to the minimum dimensionof a particle.

“biomaterial” (a.k.a. biological material) may refer to biologicalmatter, biomass, biomolecule, and organic material (i.e. derived fromliving things or containing carbon).

“Integrated circuits (IC)” means a miniaturized electronic circuit thathas been manufactured in the surface of a thin substrate ofsemiconductor material.

“hybrid integrated circuit” means a miniaturized electronic circuitbonded to a substrate or circuit board.

“nanowire” means a wire of dimensions of the order of a nanometer (10⁻⁹meters). Alternatively, nanowires can be defined as structures that havea lateral size constrained to tens of nanometers or less and anunconstrained longitudinal size. Nanowires include metallic (e.g., Ni,Pt, Au), semiconducting (e.g., InP, Si, GaN, etc.), and insulating(e.g., SiO₂, TiO₂). Molecular nanowires are composed of repeatingmolecular units either organic (e.g. DNA) or inorganic (e.g.Mo₆S_(9-x)I_(x)). “domain size” means the minimum dimension of aparticular material morphology. In the case of powders, the domain sizeis the grain size. In the case of whiskers and fibers, the domain sizeis the diameter. In the case of plates and films, the domain size is thethickness.

“nanopowder” (a.k.a. “nanosize powders,” “nanoparticles,” and “nanoscalepowders”) means and refer to fine powders that have a mean size lessthan 250 nanometers. For example, in some embodiments, the nanopowdersare powders that have particles with a mean domain size less than 100nanometers and with an aspect ratio ranging from 1 to 1,000,000. Purepowders, as the term used herein, are powders that have compositionpurity of at least 99.9% by metal basis. For example, in someembodiments the preferred purity is 99.99%.

“Powder” (a.k.a. “powder”, “particle”, and “grain”) are usedinterchangeably and encompass oxides, carbides, nitrides, borides,chalcogenides, halides, metals, intermetallics, ceramics, polymers,alloys, and combinations thereof. These terms include single metal,multi-metal, and complex compositions. These terms further includehollow, dense, porous, semi-porous, coated, uncoated, layered,laminated, simple, complex, dendritic, inorganic, organic, elemental,non-elemental, composite, doped, undoped, spherical, non-spherical,surface functionalized, surface non-functionalized, stoichiometric, andnon-stoichiometric forms or substances. Further, the term powder in itsgeneric sense includes one-dimensional materials (fibers, tubes; etc.),two-dimensional materials (platelets, films, laminates, planar, etc.),and three-dimensional materials (spheres, cones, ovals, cylindrical,cubes, monoclinic, parallelolipids, dumbbells, hexagonal, truncateddodecahedron, irregular shaped structures, etc.). The term metal usedabove includes any alkali metal, alkaline earth metal, rare earth metal,transition metal, semi-metal (metalloids), precious metal, heavy metal,radioactive metal, isotopes, amphoteric element, electropositiveelement, cation-forming element, and includes any current or futurediscovered element in the periodic table.

“Precursor” means any raw substance that can be transformed into apowder of same or different composition. In certain embodiments, theprecursor is a liquid. The term precursor includes, but is not limitedto, organometallics, organics, inorganics, solutions, dispersions,melts, sols, gels, emulsions, or mixtures.

“nanofiller” (a.k.a. nanostructured filler) means a structure orparticle intimately mixed with a matrix to form a nanostructuredcomposite. At least one of the nanostructured filler and thenanostructured composite has a desired material property which differsby at least 20% from the same material property for a micron-scalefiller or a micron-scale composite, respectively. The desired materialproperty is selected from the group consisting of refractive index,transparency to light, reflection characteristics, resistivity,permittivity, permeability, coercivity, B—H product, magnetichysteresis, breakdown voltage, skin depth, curie temperature,dissipation factor, work function, band gap, electromagnetic shieldingeffectiveness, radiation hardness, chemical reactivity, thermalconductivity, temperature coefficient of an electrical property, voltagecoefficient of an electrical property, thermal shock resistance,biocompatibility and wear rate. The nanostructured filler may compriseone or more elements selected from the s, p, d, and f groups of theperiodic table, or it may comprise a compound of one or more suchelements with one or more suitable anions, such as aluminum, antimony,boron, bromine, carbon, chlorine, fluorine, germanium, hydrogen, indium,iodine, nickel, nitrogen, oxygen, phosphorus, selenium, silicon, sulfur,or tellurium. The matrix may be a polymer (e.g., poly(methylmethacrylate), poly(vinyl alcohol), polycarbonate, polyalkene, orpolyaryl), a ceramic (e.g., zinc oxide, indium-tin oxide, hafniumcarbide, or ferrite), or a metal (e.g., copper, tin, zinc, or iron).Loadings of the nanofiller may be as high as 95%, although loadings of80% or less are preferred. The invention also comprises devices whichincorporate the nanofiller (e.g., electrical, magnetic, optical,biomedical, and electrochemical devices).

“coating” (a.k.a. “film”, “laminate”, or “layer”) means any depositioncomprising submicron and nanoscale powders. The term includes in itsscope a substrate, surface, deposition, or a combination thereof havinga hollow, dense, porous, semi-porous, coated, uncoated, simple, complex,dendritic, inorganic, organic, composite, doped, undoped, uniform,non-uniform, surface functionalized, surface non-functionalized, thin,thick, pretreated, post-treated, stoichiometric, or non-stoichiometricform or morphology.

“agglomerated” means a powder in which at least some individualparticles of the powder adhere to neighboring particles, primarily byelectrostatic forces.

“aggregated” means a powder in which at least some individual particlesare chemically bonded to neighboring particles.

“supramolecular electronics” means the assemblies of pi-conjugatedsystems on the 5 to 100 nanometer length scale that are prepared byself-assembly with the aim to fit these structures between electrodes.

“biosensor” means a device for the detection of an analyte that combinesa biological component with a physicochemical detector component. Abiosensor comprises three parts: (i) a sensitive biological element(i.e. biological material, including but not limited to, tissue,microorganisms, organelles, cell receptors, enzymes, antibodies, nucleicacids, amino acids, etc) or a biologically derived material or biomimic;(ii) a transducer; (iii) a detector element (i.e. chemical,physiochemical, optical, piezoelectric, electrochemical; thermometric,or magnetic).

“optical biosensor” means a biosensor that utilizes the behavior andproperties of light and the interaction of light with matter as thedetector element.

“optical switch” means a switch that enables signals in optical fibersor integrated optical circuits (IOCs) to be selectively switched fromone circuit to another.

“interface” means the boundary between two or more entities.

“pi-conjugated systems” (a.k.a. “stacking”) means the noncovalentinteraction between organic compounds containing aromatic moieties. π-πinteractions are caused by intermolecular overlapping of p-orbitals inπ-conjugated systems, so they become stronger as the number ofπ-electrons increases.

“quantum dots” means a semiconductor nanostructure that confines themotion of conduction band electrons, valence band holes, or excitons(pairs of conduction band electrons and valence band holes) in all threespatial directions. The confinement can be due to electrostaticpotentials (generated by external electrodes, doping, strain,impurities), due to the presence of an interface between differentsemiconductor materials (e.g. in the case of self-assembled quantumdots), due to the presence of the semiconductor surface (e.g. in thecase of a semiconductor nanocrystal), or due to a combination of these.A quantum dot has a discrete quantized energy spectrum.

“molecular self-assembly” means the assembly of molecules withoutguidance or management from an outside source.

“nanocomposite” means materials that are created by introducingnanoparticulates into a macroscopic sample material. The nanomaterialsadd to the electrical and thermal conductivity as well as to themechanical strength properties of the original material. In general, thenanomaterial used are carbon nanotubes and they are dispersed into theother composite materials during processing. The percentage by weight ofthe nanomaterials introduced is able to remain very low (on the order of0.5%-5%) due to the incredibly high surface area to volume ratio of theparticles.

“molecular electronics” (a.k.a. moletronics) means an interdisciplinarythemed materials science in which the unifying feature is the use ofmolecular building blocks for the fabrication of electronic components,both passive (e.g. resistive wires) and active (e.g transistors).Molecular electronics provides a means to extend Moore's Law beyond theforeseen limits of small-scale conventional silicon integrated circuits.

“Moore's law” means the empirical observation made in 1965 that thenumber of transistors on an integrated circuit for minimum componentcost doubles every 24 months. It is attributed to Gordon E. Moore (born1929), a co-founder of Intel.

“supramolecular chemistry” means the area of chemistry which focuses onthe noncovalent bonding interactions of molecules. Traditional organicsynthesis involves the making and breaking of covalent bonds toconstruct a desired molecule.

“molecular recognition” means a chemical event in which a host moleculeis able to form a complex with a second molecule (i.e. the guest). Thisprocess occurs through non-covalent chemical bonds, including but notlimited to, hydrogen bonding, hydrophobic interactions, ionicinteraction.

“static molecular recognition” means a 1:1 type complexation reactionbetween a host molecule and a guest molecule (an analogy is theinteraction between a key and a keyhole.) To achieve advanced staticmolecular recognition, it is necessary to make recognition sites thatare specific for guest molecules.

“dynamic molecular recognition” means a reaction that dynamicallychanges the equilibrium to an n:m type host-guest complex by arecognition guest molecule. Dynamic molecular recognition appearing insupermolecules is essential for designing highly functional chemicalsensors and molecular devices.

“rotaxane” means a mechanically-interlocked molecular architectureconsisting of a dumbbell-shaped molecule that is threaded through amacrocycle or ring-like molecule. The two components are kineticallytrapped as the two end-groups of the dumbbell (often called stoppers)are larger than the internal diameter of the ring, and thus preventdissociation (unthreading) since this would require significantdistortion of the covalent bonds. The name, rotaxane, is derived fromthe Latin for wheel (rota) and axle (axis).

“synthetic molecular motors” means nanoscale devices capable of rotationunder energy input. The basic requirements for a synthetic motor arerepetitive 360° motion, the consumption of energy, and unidirectionalrotation. Examples include but are not limited to triptycence motors andhelicene.

“bar code” means a code representing characters by sets of parallel barsof varying thickness and separation that are read optically bytransverse scanning.

“calibration” means ensuring continuous adequate performance of sensing,measurement, and actuating equipment with regard to specified accuracyand precision requirements.

“certification” means technical evaluation, made as part of and insupport of the accreditation process that establishes the extent towhich a particular computer system or network design and implementationmeet a pre-specified set of requirements.

“validation” means establishing documented evidence which provides ahigh degree of assurance that a specific process will consistentlyproduce a product meeting its predetermined specifications and qualityattributes.

“Batch” means a specific quantity of a drug or other material that isintended to have uniform character and quality, within specified limits,and is produced according to a single manufacturing order during thesame cycle of manufacture.

“Component” means any ingredient intended for use in the manufacture ofa drug product, including those that may not appear in such drugproduct.

“Drug product” means a final formulation that contains an active drugingredient generally, but not necessarily, in association with inactiveingredients. The term also includes a finished dosage form that does notcontain an active ingredient but is intended to be used as a placebo.

“Active ingredient” means any component that is intended to furnishpharmacological activity or other direct effect in the diagnosis, cure,mitigation, treatment, or prevention of disease, or to affect thestructure or any function of the body of man or other animals. The termincludes those components that may undergo chemical change in themanufacture of the drug product and be present in the drug product in amodified form intended to furnish the specified activity or effect.

“Inactive ingredient” means any component other than an activeingredient.

“In-process material” means any material fabricated, compounded,blended, or derived by chemical reaction that is produced for, and usedin, the preparation of the drug product.

“Lot number, control number, or batch number” means any distinctivecombination of letters, numbers, or symbols, or any combination thereof,from which the complete history of the manufacture, processing, packing,holding, and distribution of a batch or lot of drug product or othermaterial can be determined.

“Quality control unit” means any person or organizational elementdesignated by the firm to be responsible for the duties relating toquality control.

“Acceptance criteria” means the product specifications andacceptance/rejection criteria, such as acceptable quality level andunacceptable quality level, with an associated sampling plan, that arenecessary for making a decision to accept or reject a lot or batch.

“Process analytical technology” (a.k.a. PAT) means a mechanism todesign, analyze, and control pharmaceutical manufacturing processesthrough the measurement of critical process parameters and qualityattributes.

“New molecular entity” (a.k.a. NME or New Chemical Entity (“CNE”)) meansa drug that contains no active moiety that has been approved by FDA. Anactive moiety means the molecule or ion, excluding those appendedportions of the molecule that cause the drug to be an ester, salt(including a salt with hydrogen or coordination bonds), or othernoncovalent derivative (such as a complex, chelate, or clathrate) of themolecule, responsible for the physiological or pharmacological action ofthe drug substance.

“pH” means is a measure of the activity of hydrogen ions (H⁺) in asolution and, therefore, its acidity.

“Encapsulation” means a range of techniques used to enclose medicines ina relatively stable shell, allowing them to, for example, be takenorally or be used as suppositories. The two main types of capsules arehard-shelled capsules, which are normally used for dry, powderedingredients, and soft-shelled capsules, primarily used for oils and foractive ingredients that are dissolved or suspended in oil. Both of theseclasses of capsule are made both from gelatine and from plant-basedgelling substances like carrageenans and modified forms of starch andcellulose.

“Route of administration” means the path by which a drug product, fluid,poison, or other substance is brought into contact with the body.

“Pharmaceutical formulation” means the process in which differentchemical substances are combined to a pure drug substance to produce afinal drug product.

“Dosage form” means the physical form of a dose of a drug product, suchas a capsule or injection. The route of administration is dependent onthe dosage form of a given drug. Examples of dosage forms of theinvention are set forth in Table I.

“Excipient” means an inactive substance used as a carrier for the activeingredients in a drug such as vaccines. Excipients are also sometimesused to bulk up formulations with very potent active ingredients, toallow for convenient and accurate dosage. Examples of excipients,include but are not limited to, antiadherents, binders, coatings,disintegrants, fillers, dilutents, flavors, colors, lubricants, andpreservatives.

“Vehicle” means the excipients or matrix in which the active ingredientis prepared (e.g., normal saline).

“Potency” means substantively, the strength of a drug (i.e. vaccine) butmore complex. It is not a factor proportional to the concentration ofthe active ingredient (antigen) but rather to the immunogenicity of thedrug product (formulated antigen). So, just saying there is 300 mg ofgp120 or 1 mg of DNA there in the vial isn't sufficient, the question is“is it immunogenic”? For a background on potency testing of vaccines,See, Habig, Veterinary Microbiology, 37:343-51:1993. It concludes that apotency test should be reasonably predicative of efficacy in humans,i.e., measure a parameter that correlates with efficacy. Anotherimportant aspect to remember is that it should be sufficientlyquantitative, so that it can be determined if your vaccine has lost 30%,50%, or 70% potency, for example.

“Bulk” (a.k.a. Drug Substance) means the drug substance or the drugproduct which has not been filled into final containers fordistribution. Final formulated bulk generally refers to drug productwhich is formulated and being stored or held prior to filling. Drugsubstance may be stored or held as “bulk” or “concentrated bulk” priorto formulation into drug product.

II.) Nanomaterial

The present invention provides for nanomaterials which are manufacturedto achieve a desired function or property that will assist in thepackaging of drug products. Nanomaterials of the inventions comprisenanostructures, nanocrystals, nanowires, nanotubes, nanofillers,nanocomposites, and precursors or any combination thereof. Thenanomaterials useful in the present invention can also further compriseligands conjugated, cooperated, associated or attached to their surfaceas described throughout. Suitable ligands include any group known tothose skilled in the art. Use of such ligands can enhance the ability ofthe nanocrystals to incorporate into various solvents and matrixes,including polymers. Increasing the miscibility (i.e., the ability to bemixed without separation) of the nanocrystals in various solvents andmatrixes allows them to be distributed throughout a polymericcomposition such that the nanocrystals do not aggregate together andtherefore do not scatter light. Such ligands are described as“miscibility-enhancing” ligands herein.

In a further embodiment, the invention provides polymeric layerscomprising a polymer and nanocrystals embedded within the polymer, suchthat the layers act as photon-filtering nanocomposites. Suitably, thenanocrystals will be prepared from semiconductor materials, but anysuitable material described throughout can be used to prepare thenanocrystals. In certain embodiments, the nanocrystals will have a sizeand a composition such that the nanocrystals absorb light of aparticular wavelength or over a range of wavelengths. As such, thenanocrystals utilized in these embodiments are tailored such that theirabsorption characteristics are enhanced or maximized, while theiremission characteristics are minimized, i.e. they will absorb light in ahighly efficient manner, but suitably will emit only a very low level,or preferably no light. In other embodiments, however, thephoton-filtering nanocomposites can also comprise nanocrystals that havehigh emission properties and emit light at a particular wavelength asdiscussed throughout. As such, the present invention providesnanocomposites that comprise different types of nanocrystals such thatthe nanocomposites exhibit several, or all, of the properties discussedthroughout, in a layer. In embodiments of the present invention wherethe photon-filtering polymeric layers are used to coat pharmaceuticaldosage forms, such dosage forms can be refractive (e.g., lenses) orreflective (e.g., mirrors).

Additionally, in certain embodiments of the present invention where thephoton-filtering polymeric layers are used to encapsulate drug products,such drug products can be enclosed in any dosage form known to theskilled artisan.

By controlling the size and composition of the nanocrystals used in thepractice of the present invention, the nanocrystals will absorb light ofa particular wavelength, or a particular range of wavelengths, while notscattering light. The ability to make nanocrystals out of differentsemiconductors, and control their size, allows for pharmaceutical dosageforms to be fabricated with nanocrystals that will absorb light from theUV, to visible, to near infrared (NIR), to infrared (IR) wavelengths.Nanocrystals for use in the present invention will suitably be less thanabout 100 nm in size, and down to less than about 2 nm in size. Insuitable embodiments, the nanocrystals of the present invention absorbvisible light. As used herein, visible light is electromagneticradiation with wavelengths between about 380 and about 780 nanometersthat is visible to the human eye. Visible light can be separated intothe various colors of the spectrum, such as red, orange, yellow, green,blue, indigo and violet. The photon-filtering nanocomposites of thepresent invention can be constructed to absorb light that makes up anyone or more of these colors. For example, the nanocomposites of thepresent invention can be constructed to absorb blue light, red light, orgreen light, combinations of such colors, or any colors in between. Asused herein, blue light comprises light between about 435 nm and about500 nm, green light comprises light between about 520 nm and 565 nm andred light comprises light between about 625 nm and about 740 nm inwavelength. One of ordinary skill will be able to constructnanocomposites that can filter any combination of these wavelengths, orwavelengths between these colors, and such nanocomposites are embodiedby the present invention.

As disclosed herein, the nanocrystals useful in the practice of thepresent invention can have a composition and a size such that theyabsorb light at a particular wavelength(s) and emit at a particularwavelength(s). In certain embodiments, the dosage forms of the presentinvention can comprise combinations of nanocrystals that function in thevarious ways described herein. For example, a nanocomposite of thepresent invention can comprise nanocrystals having specific, enhancedemission properties, others having specific, enhanced absorptionproperties but low emission properties, and the entire nanocomposite canbe constructed such that the layer has a specific refractive index thatis matched or tailored for a specific purpose. Combined in such a way,the pharmaceutical dosage forms of the present invention can be used asencapsulates for drug products (e.g. biologics, vaccines andinjectables, blood products, diagnostic products, antibiotics,anti-inflammatory medicines etc.).

In preferred embodiments, it is desirable that the nanocrystals do notaggregate. That is, that they remain separate from each other in thedosage form and do not coalesce with one another to form largeraggregates. This is important, as individual crystals will not scatterlight passing through the layer, while larger aggregated structures cancreate an opaque layer that can hinder the passage of light. However,depending on the parameters and individual specifications of the dosageform in which the nanomaterials are used the degree of aggregation mayneed to be modified to achieve the desired result.

Dispersion of nanocrystals into the drug product can be controlled byminimizing phase separation and aggregation that can occur wheninterfacing (physical) the nanocrystals with the drug product. A basicstrategy known in the art is to design a 3-part ligand, in which thehead-group, tail-group and middle/body-group can each be independentlyfabricated and optimized for their particular function, and thencombined into an ideally functioning complete surface ligand. In onembodiment, the head group is selected to bind specifically to thematerial of the nanocrystal (or nanocrystal dosage form as the case maybe). In one embodiment, the tail group is designed to interact stronglywith the drug product and be miscible in the solvent utilized (and can,optionally, contain a linker group to the drug product) to allow maximummiscibility and loading density in the drug product without nanocrystalaggregation. In one embodiment, the middle or body group is selected forspecific electronic functionality (e.g., charge isolation, Input/output,detector, etc).

In another aspect of the invention nanomaterials comprise nanowires.While the example implementations described herein principally use Si,other types of nanowires (and other nanostructures such as nanoribbons,nanotubes, nanorods and the like) can be used including semiconductivenanowires, that are comprised of semiconductor material selected from,e.g., Si, Ge, Sn, Se, Te, B, C (including diamond), P, B—C, B—P(BP6),B—Si, Si—C, Si—Ge, Si—Sn and Ge—Sn, SiC, BN/BP/BAs, AlN/AlP/AlAs/AlSb,GaN/GaP/GaAs/GaSb, InN/InP/InAs/InSb, BN/BP/BAs, AlN/AlP/AlAs/AlSb,GaN/GaP/GaAs/GaSb, InN/InP/InAs/InSb, ZnO/ZnS/ZnSe/ZnTe, CdS/CdSe/CdTe,HgS/HgSe/HgTe, BeS/BeSe/BeTe/MgS/MgSe, GeS, GeSe, GeTe, SnS, SnSe, SnTe,PbO, PbS, PbSe, PbTe, CuF, CuCl, CuBr, CuI, AgF, AgCl, AgBr, AgI,BeSiN2, CaCN2, ZnGeP2, CdSnAs2, ZnSnSb2, CuGeP3, CuSi2P3, (Cu, Ag)(Al,Ga, In, Tl, Fe)(S, Se, Te)2, Si3N4, Ge3N4, Al.sub.2O.sub.3, (Al, Ga,In)2 (S, Se, Te)3, Al2CO, and an appropriate combination of two or moresuch semiconductors.

Additionally, the nanowires of the invention can include carbonnanotubes, or conductive or semiconductive organic polymer materials,(e.g., pentacene, and transition metal oxides).

In another aspect of the invention, nanomaterials of the inventioncomprise nanotubes. Nanotubes can be formed in combinations/thin filmsof nanotubes as is described herein for nanowires, alone or incombination with nanowires, to provide the properties and advantagesdescribed herein.

a. Functional Properties of Nanomaterials

In one aspect of the invention nanomaterials are fabricated to create apharmaceutical dosage form (Table I). One of ordinary skill in the artwill appreciate that the entire dosage form may comprise nanomaterialsor the dosage form will consist of nanomaterials to achieve the desiredfunctions described herein. In one embodiment, the nanomaterial isdesigned to include a functional property. The preferred functionalproperty is one that provides a synergy with the dosage form and thedrug product that the nanomaterial is being utilized in concert with.For example, nanomaterials may possess optical properties useful indetection of particulates or contaminates in gas or aerosols. This isparticularly useful in monitoring the quality of inhalants that havebeen in storage for some time. In another example, a nanomaterial maypossess thermal properties whereby deviations in temperature may bedetected. This is particularly useful for drug products that aredependent on temperature for viability (i.e. vaccines, blood products).

A very wide variety of pure phase materials such as polymers are nowreadily known in the art. However, low cost pure phase materials aresomewhat limited in the achievable ranges of a number of properties,including, for example, electrical conductivity, magnetic permeability,dielectric constant, and thermal conductivity. In order to circumventthese limitations, it has become common to form composites, in which amatrix is blended with a filler material with desirable properties.

In one embodiment, the invention comprises a nanofiller, intimatelymixed with a matrix to form a nanostructured composite. At least one ofthe nanostructured filler and the nanostructured composite has a desiredmaterial property which differs by at least 20% from the same materialproperty for a micron-scale filler or a micron-scale composite,respectively. The desired material property is selected from the groupconsisting of refractive index, transparency to light, reflectioncharacteristics, resistivity, permittivity, permeability, coercivity,B—H product, magnetic hysteresis, breakdown voltage, skin depth, curietemperature, dissipation factor, work function, band gap,electromagnetic shielding effectiveness, radiation hardness, chemicalreactivity, thermal conductivity, temperature coefficient of anelectrical property, voltage coefficient of an electrical property,thermal shock resistance, biocompatibility and wear rate.

The nanofiller may comprise one or more elements selected from the s, p,d, and f groups of the periodic table, or it may comprise a compound ofone or more such elements with one or more suitable anions, such asaluminum, antimony, boron, bromine, carbon, chlorine, fluorine,germanium, hydrogen, indium, iodine, nickel, nitrogen, oxygen,phosphorus, selenium, silicon, sulfur, or tellurium. The matrix may be apolymer (e.g., poly(methyl methacrylate), poly(vinyl alcohol),polycarbonate, polyalkene, or polyaryl), a ceramic (e.g., zinc oxide,indium-tin oxide, hafnium carbide, or ferrite), or a metal (e.g.,copper, tin, zinc, or iron). Loadings of the nanofiller may be as highas 95%, although loadings of 80% or less are preferred. The inventionalso comprises devices which incorporate the nanofiller (e.g.,electrical, magnetic, optical, biomedical, and electrochemical devices).

(i) Nanomaterial with Thermal Conductivity

In one aspect of the invention, the nanomaterial possesses thefunctional property of thermal conductivity. Any nanoparticle that canbe functionalized and which has a higher thermal conductivity than theorganic matrix can be used to prepare the present compositions. Suitablenanoparticles include but are not limited to colloidal silica,polyhedral oligomeric silsesquioxane (“POSS”), nano-sized metal oxides(e.g. alumina, titania, zirconia), nano-sized metal nitrides (e.g. boronnitrides, aluminum nitrides) and nano-metal particles (e.g., silver,gold, or copper nanoparticles). In particularly useful embodiments, thenanoparticles are organo-functionalized POSS materials or colloidalsilica. Colloidal silica exists as a dispersion of submicron-sizedsilica (SiO₂) particles in an aqueous or other solvent medium. Thecolloidal silica contains up to about 85 weight % of silicon dioxide(SiO₂) and typically up to about 80 weight % of silicon dioxide. Theparticle size of the colloidal silica is typically in a range betweenabout 1 nanometers (“nm”) and about 250 nm, and more typically in arange between about 5 nm and about 150 nm. The fillers used aremicron-sized thermally conductive materials and can be reinforcing ornon-reinforcing. In one embodiment, the present nanomaterial withthermal functionality can be formed into sheets and cut into any desiredshape. In a preferred embodiment, the nanomaterials can advantageouslybe used for thermal interface pads and positioned on thermal biosensors.In a further embodiment, the thermal interface pad and thermal biosensoris fabricated into a pharmaceutical dosage form to monitor temperatureof the drug product enclosed therein.

(ii) Nanomaterial with Porosity/Permeability

In one embodiment, nanomaterials posses predefined porosity andpermeability properties. The properties are useful in the design offilters that are fabricated into pharmaceutical dosage forms. The filerscan be used for such process as purification, etc. The nanomaterials aredesigned with a membrane or layer that is designed to block certainobjects or substances while letting others through. Theporosity/permeability properties of the nanomaterials can be used toseparate liquids from liquids, solids from liquids, gas from liquids, orany combination of thereof. In a preferred embodiment, theporosity/permeability properties are designed to be advantageous tomonitor the quality (such as purity, potency, etc) of the drug productenclosed within the dosage form.

(iii) Nanomaterial with enhanced luminescence

In one embodiment, nanomaterials posses enhanced luminescent properties.The nanomaterials are made from nanopowders using standard methods knownin the art. For example, luminescent nanomaterial is prepared using thefollowing steps: forming a homogenized precursor solution of at leastone lanthanide group metal precursor and at least one lanthanide seriesdopant precursor; adding a phosphate source and a fuel to the precursorsolution; removing water from the precursor solution to leave a reactionconcentrate; and igniting the reaction concentrate to form a powdercomprising the plurality of nanoparticles. The nanomaterials of theinvention can be used in pharmaceutical dosage form applications suchas, display devices and imaging applications positioned on thepharmaceutical dosage form itself. In a preferred embodiment, thenanomaterials will be used in the quality monitoring of pharmaceuticaldosage forms. In a further embodiment, the nanomaterial will display apre-determined schema when the quality of the pharmaceutical dosage formis outside the scope of the quality parameters set forth by the qualitycontrol protocol. It will be readily apparent to one of skill in the artthat the schema can comprise a wide array of displays, including but notlimited to, changing colors (including but not limited to red, blue, andgreen), displaying a symbol (e.g. and “X”), displaying a word (e.g.“EXPIRED”).

(iv) Nanomaterial with Enhanced Acoustics

In one embodiment, nanomaterials posses enhanced acoustic functions. Thenanomaterials are made from using standard methods known in the art. Forexample, a surface acoustic wave device fabricated on a lithium niobatesubstrate and a sensing bilayer positioned on the acoustic path of thesurface acoustic wave device, the sensing bilayer further comprisingnanocrystalline or other nanomaterial such as nanoparticles or nanowiresof palladium and metal free phthalocyanine. Preferably, the surfaceacoustic wave device has a center frequency of about 200 MHz.Nanomaterials with enhanced acoustic properties will respond to gases(i.e. hydrogen, helium, etc.) in near real time, at low (room)temperature, without being affected by CO₂, CH₄ and other gases, in airambient or controlled ambient, providing sensitivity to low ppm levels.In a preferred embodiment, the nanomaterials detect and monitor gasesenclosed in pharmaceutical dosage forms described herein. In a furtherembodiment, the nanomaterial displays a pre-determined schema when thequality of the pharmaceutical dosage form is outside the scope of thequality parameters set forth by the quality control protocol.

(v) Nanomaterial with Enhanced Magnetic Properties

In one embodiment, nanomaterials posses enhanced magnetic functions. Thenanomaterials are made from using standards known in the art. Forexample, a solvent, preferably an ether or an aromatic solvent such astoluene, anisole, dioctylether, or the like, is added to a carboxylicacid, preferably Oleic acid, or the like. An amine, preferablyOleylamine or the like is then added to the solvent and Oleic acidsolution to complete solution A. It will be appreciated that othersolvents or amines not listed here may be used to perform the samedecomposition. The solution A is added to a metal-organic precursor toform solution B. Solution B is then heated, for example by radiation atapproximately 150 degrees C. in anisole for approximately 48 hours,under pressure, for example 3 Bars of H2. Nanorods begin to appear. Thenanorods are crystalline hexagonal close packed (hcp), and grow alongthe c axis of the structure. The nanorods are in a thermodynamicallystable form of cobalt after completion of the reaction. Thesethermodynamically stable cobalt nanorods will not rearrange into otherforms such as spherical nanoparticles or any other form.

The nanoparticles that result from this embodiment exhibit magneticproperties, such as for example: i) saturation magnetization similar tothe magnetic characteristics and properties of bulk cobalt; ii) enhancedmagnetic anisotropy and strongly enhanced coercive magnetic field (ascompared to bulk cobalt and spherical nanoparticles) due to the shapeanisotropy. The nanomaterials with enhanced magnetic properties willallow particle orientation in magnetic fields to optimize high-frequencydevice applications. In a preferred embodiment, the high-frequencydevice is fabricated into a pharmaceutical dosage form.

(vi) Nanomaterial with Enhanced Solubility

In one embodiment, nanomaterials posses enhanced solubility properties.The nanomaterials are made from using standards known in the art. Forexample, a rigid poly(aryleneethynylene) polymer is coupled with apara-diethynyl-(R₁—R_(x))arylene and an (R₁—R_(y))-para-dih-aloarylenein the presence of a first polymerization-terminating haloaryl agentunder conditions and for a period of time to produce fluorescence. Thenterminating the coupling by addition of a secondpolymerization-terminating haloaryl agent, the second haloaryl agenthaving equal or greater activity for coupling as compared to the(R₁—R_(y))-para-dihaloarylene. The nanomaterials with enhancedsolubility will provide for functional nanomaterials that can be usedfor epoxy and engineering plastic composites, filters, actuators,adhesive composites, elastomer composites, materials for thermalmanagement (interface materials, materials for heat transferapplications), improved dimensionally stable structures forsensorsoptoelectronic or microelectromechanical components orsubsystems, rapid prototyping materials, composite fibers, etc. In apreferred embodiment, the nanomaterial is fabricated in a pharmaceuticaldosage form. In a further embodiment, the nanomaterial with enhancedsolubility properties is used to monitor quality of the drug productenclosed within the pharmaceutical dosage form.

(vii) Shape Engineered Nanomaterials

In one embodiment, nanomaterials are engineered for specific shapes ormechanical properties. The nanomaterials are made from using standardsknown in the art. For example, nanomaterials are made with modifieddegree of agglomeration. Additionally, nanomaterials are made with amodified surface area. Additionally, nanomaterials are made withpost-processing to modify the phase and shape. Additionally,post-processing is utilized to achieve consolidation. Nanomaterials thatare shape engineered are used for ceramic, metal, or composite seals onpharmaceutical dosage forms. Additionally as filters with a definedporosity gradient, monitors, sensors, drug delivery devices, andbiocatalysts from nanoscale powders using the multi-layer laminatingprocess to produce three-dimensional shapes. In a preferred embodiment,the nanomaterials are used in pharmaceutical dosage forms. In a furtherembodiment, the nanomaterials monitor quality of drug products enclosedwithin the pharmaceutical dosage form.

(viii) Nanomaterials will Enhanced Optical Properties

In one embodiment, nanomaterials are engineered with enhanced opticalproperties. The nanomaterials are made from using standards known in theart. Generally, in optical lenses, the optical path length varies withdistance from its center, where optical path length is defined as theproduct of the physical path length, thickness, and the refractiveindex, n, of the lens material. In the most common lenses, therefractive index, n, is fixed and the thickness, varies. However, a lenscan also be created by keeping the thickness, constant and varying therefractive index as a function of distance from the axis of the lens.Such a lens is called a Graded Index lens, or sometimes abbreviated as aGRIN lens. The methods of the present invention can also be used tocreate GRIN lenses.

Polymer/nanocrystal blends can be used to make GRIN lenses due to thedramatic refractive index difference between nanocrystals (e.g., ZnSabout 2.35) and optical plastics such as poly(methyl methacrylate)(PMMA) (refractive index about 1.45). With normal glass, a difference ofabout 0.05 refractive index units is achievable over about 8 mm.Utilizing the methods and processes of the present application, adifference of about 0.20 refractive index units over about 8 mm can beachieved to make much more powerful lenses. Nanomaterials with enhancedoptical properties can be used for contact sensors, remote sensors,LIDAR, optical parametric oscillators, optical data storage, opticalspectroscopy, optical amplifiers, wavelength translation devices, supersensitive optical detection, and optical switches. In a preferredembodiment, the sensors with enhanced optical properties are fabricatedinto pharmaceutical dosage forms. In a further embodiment, the opticallyenhanced nanomaterials are used to monitor quality of the drug productsenclosed within the pharmaceutical dosage forms described herein.

III.) Sensors

In one embodiment, the invention relates to sensors that are fabricatedinto pharmaceutical dosage forms. In a preferred embodiment, the sensorsare made from nanomaterials disclosed herein and are developed on amicroscopic scale using MEMS (micro-electrical-mechanical-systems)technology. In one embodiment, the sensor is made from 1^(st) generationMEMS technology (i.e. a sensor element mostly based on a silicon orsimilar structure, sometimes combined with analog amplification on ananomaterial). In one embodiment, the sensor is made from 2^(nd)generation MEMS technology (i.e. a sensor element combined with analogamplification and analog-to-digital converter on one nanomaterial). In apreferred embodiment, the sensor is made from 3^(rd) generation MEMStechnology (i.e. fusion of the sensor element with analog amplification,analog-to-digital converter and digital intelligence for linearizationand temperature compensation on the same nanomaterial). In anotherpreferred embodiment, the sensor is made from 4^(th) generation MEMStechnology (i.e. memory cells for calibration and temperaturecompensation data are added to the elements of the 3^(rd) generationsensor). The advantages of using sensors made out of nanomaterials isthe sensors can reach significantly higher speeds and sensitivity thatmacroscale sensors. In addition, the scale of the pharmaceutical dosageforms disclosed herein make use of nanosensors optimal.

It will be appreciated by one of skill in the art that the type ofsensor needed will be a direct function to the pharmaceutical dosageform that is being used and the drug product that is being monitored.For example, monitoring the potency of a vaccine will require differentmonitoring parameters that monitoring the pH of an antibiotic which inturn will require different monitoring parameters that monitoring thetemperature of a blood product. In these situations, it will beappreciated by one of ordinary skill that either (i) the same sensorscan be used with different detecting criteria or (ii) different types ofsensors can be used to achieve the best level of monitoring for aspecific pharmaceutical dosage form.

Accordingly, sensors of the present invention comprise thermal,electromagnetic, mechanical, chemical, optical, radiation, acoustic, andbiological sensors. In one embodiment, thermal sensors include but arenot limited to thermometers, thermocouples, temperature sensitiveresistors, bolometers, calorimeter.

In a further embodiment, electromagnetic sensors include but are notlimited to ohmmeters, multimeters, galvanometers, ammeters, leafelectroscopes, watt-hour meters, magnetic compasses, fluxgate compasses,magnetometers, and metal detectors.

In a further embodiment, mechanical sensors include but are not limitedto barometers, barographs, pressure gauges, air speed indicators, rateof change sensors, flow sensors, anemometers, flow meters, gas meters,water meters, mass flow sensors, acceleration sensors, whisker sensors,Quadrature wheels, and positions switches.

In a further embodiment, chemical sensors include but are not limited tooxygen sensors (a.k.a. λ sensors), ion-selective electrodes, pH glasselectrodes, and redox electrodes.

In a further embodiment, optical and radiation sensors include but arenot limited to RADAR, LIDAR, dosimeters, particle detectors,scintillators, wire chambers, cloud chambers, bubble chambers, infraredsensors, photocells, photodiodes, phototransistors, image sensors;vacuum tube devices, and proximity sensors.

In a further embodiment, acoustic sensors include but are not limited toultrasounds and SONAR.

In a further embodiment, biological sensors include but are not limitedto biosensors that can detect physical aspects of the externalenvironment such as light, motion, temperature, magnetic fields,gravity, humidity, vibration, pressure, electrical fields, and sound.Additionally, biosensors that can detect environmental molecules such astoxins, nutrients, and pheromones are within the scope of the invention.Additionally, biosensors that can detect metabolic parameters such asglucose level and oxygen level are within the scope of the invention.

In another aspect, this invention also includes a method of producing animproved sensor device. A non-stoichiometric nanopowder is sonicated ina solvent to form a slurry. The slurry is brushed onto screen-printedelectrodes and allowed to dry at to remove the solvent. A dissolvedpolymer may also be included in the slurry. The screen-printedelectrodes may be gold electrodes on an alumina substrate. The screenmay be made from stainless steel mesh at least 8.times. 10 inches insize, with a mesh count of 400, a wire diameter of 0.0007 inches, a biasof 45.degree., and a polymeric emulsion of 0.0002 inches.

In another aspect, this invention includes an improved sensor deviceprepared from a screen printable paste. A nanopowder and polymer aremechanically mixed; a screen-printing vehicle is added to the mixtureand further mechanically mixed. The mixture is milled and screen-printedonto prepared electrodes. The paste is allowed to level and dry. Thisinvention also includes the improved sensor devices produced by theabove processes.

In another aspect of the invention, thermal sensors are prepared fromnanostructured powders. These thermal sensors can be used to monitoraspects of the pharmaceutical manufacturing process including but notlimited to monitor radiation, power, heat and mass flow, charge andmomentum flow, and phase transformation.

In a preferred embodiment, the sensors disclosed herein are fabricatedinto a pharmaceutical dosage form whereby the dosage form comprise thenanomaterial or are fabricated to consist of 1%, 2%, 3%, 4%, 5%, 6%, 7%,8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%,23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%,37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%,51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%,65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%,79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% nanomaterial and the remainingingredients of the specified dosage form are known in the art.

IV.) Pharmaceutical Formulation

Pharmaceutical formulation is the process in which different chemicalsubstances are combined to a pure drug substance to produce a final drugproduct. Formulation studies involve developing a preparation of thedrug which is both stable and acceptable to the patient. For orallytaken drugs, this usually involves incorporating the drug into a tabletor a capsule. It is important to appreciate that a tablet contains avariety of other substances apart from the drug itself, and studies haveto be carried out to ensure that the drug is compatible with these othersubstances.

An excipient is an inactive substance used as a carrier for the activeingredients of a drug product. In addition, excipients can be used toaid the process by which a drug product is manufactured. The activesubstance is then dissolved or mixed with an excipient. Excipients arealso sometimes used to bulk up formulations with very potent activeingredients, to allow for convenient and accurate dosage. Once theactive ingredient has been purified, it cannot stay in purified form forvery long. In many cases it will denature, fall out of solution, orstick to the sides of the container. To stabilize the active ingredient,excipients are added to ensure that the active ingredient stays active,and is stable for a long enough period of time that the shelf-life ofthe product makes it competitive with other products and safe for theend-user. Examples of excipients, include but are not limited to,anti-adherents, binders, coatings, disintegrants, fillers, diluents,flavors, colors, lubricants, and preservatives. The final formulationcomprises and active ingredient and excipients which are then enclosedin the pharmaceutical dosage form.

Pre-formulation involves the characterization of a drug's physical,chemical, and mechanical properties in order to choose what otheringredients should be used in the preparation. Formulation studies thenconsider such factors as particle size, polymorphism, pH, andsolubility, as all of these can influence bioavailability and hence theactivity of a drug. The drug must be combined with inactive additives bya method which ensures that the quantity of drug present is consistentin each dosage unit (e.g. each tablet). The dosage should have a uniformappearance, with an acceptable taste, tablet hardness, or capsuledisintegration.

It is unlikely that these studies will be complete by the time clinicaltrials commence. This means that simple preparations are developedinitially for use in phase I clinical trials. These typically consist ofhand-filled capsules containing a small amount of the drug and adiluent. Proof of the long-term stability of these formulations is notrequired, as they will be used (tested) in a matter of days. However,long-term stability is critical in supply chain management since thetime the final formulation is packaged until it reaches the patient canbe several months or years. In addition, the location of the patient inrelation to the packaging of the drug product influences qualityfactors. Consideration has to be given to what is called the drug load(i.e. the ratio of the active drug to the total contents of the dose). Alow drug load may cause homogeneity problems. A high drug load may poseflow problems or require large capsules if the compound has a low bulkdensity. By the time phase III clinical trials are reached, theformulation of the drug should have been developed to be close to thepreparation that will ultimately be used in the market.

A knowledge of stability is essential by this stage, and conditions musthave been developed to ensure that the drug is stable in thepreparation. If the drug proves unstable, it will invalidate the resultsfrom clinical trials since it would be impossible to know what theadministered dose actually was. Stability studies are carried out totest whether temperature, humidity, oxidation, or photolysis(ultraviolet light or visible light) have any effect, and thepreparation is analysed to see if any degradation products have beenformed. It is also important to check whether there are any unwantedinteractions between the preparation and the container. If a plasticcontainer is used, tests are carried out to see whether any of theingredients become adsorbed on to the plastic, and whether anyplasticizers, lubricants, pigments, orstabilizers leach out of theplastic into the preparation. Even the adhesives for the container labelneed to be tested, to ensure they do not leach through the plasticcontainer into the preparation. The way a drug is formulated can avoidsome of the problems associated with oral administration. Drugs arenormally taken orally as tablets or capsules. The drug (activesubstance) itself needs to be soluble in aqueous solution at acontrolled rate. Such factors as particle size and crystal form cansignificantly affect dissolution. Fast dissolution is not always ideal.For example, slow dissolution rates can prolong the duration of actionor avoid initial high plasma levels.

Accordingly, in one embodiment, the nanomaterials of the invention arefabricated into the pharmaceutical dosage form whereby the nanomaterialsare used to monitor quality of the drug product enclosed within thedosage form from the point of packaging until use by the end-user.

In a further embodiment, the nanomaterials of the invention arefabricated into a pharmaceutical dosage form whereby the nanomaterialsare used to monitor pH levels of the drug product.

In a further embodiment, the nanomaterials of the invention arefabricated into a pharmaceutical dosage form whereby the nanomaterialsare used to monitor temperature levels of the drug product.

In a further embodiment, the nanomaterials of the invention arefabricated into a pharmaceutical dosage form whereby the nanomaterialsare used to monitor stability of the drug product.

In a further embodiment, the nanomaterials of the invention arefabricated into a pharmaceutical dosage form whereby the nanomaterialsare used to monitor oxidation of the drug product.

In a further embodiment, the nanomaterials of the invention arefabricated into a pharmaceutical dosage form whereby the nanomaterialsare used to monitor degradation of the drug product.

In a further embodiment, the nanomaterials of the invention arefabricated into a pharmaceutical dosage form whereby the nanomaterialsare used to monitor leachates of the drug product.

In a further embodiment, the nanomaterials of the invention arefabricated into a pharmaceutical dosage form whereby the nanomaterialsare used to monitor potency of the drug product.

In a further embodiment, the nanomaterials of the invention arefabricated into a pharmaceutical dosage form whereby the nanomaterialsare used to monitor cold chain requirements of the drug product.

V.) Pharmaceutical Dosage Forms

A dosage form is the physical form of a dose of a drug product, such asa capsule or injection. Table I summarizes the generally recognizeddosage forms. The route of administration (See, Section VI. Entitled“Route of Administration”) is dependent on the dosage form of a givendrug. Various dosage forms may exist for the same compound, sincedifferent medical conditions may warrant different routes ofadministration. For example, persistent vomiting may make it difficultto use an oral dosage form. In this case, it may be advisable to useeither an injection or a suppository. Also, specific dosage forms may bewarranted for certain medications, since there may be problems withstability (e.g. insulin cannot be given orally since it is digested bythe stomach).

In the packaging of pharmaceuticals, encapsulation refers to a range oftechniques used to enclose medicines in a relatively stable shell,allowing them to, for example, be taken orally or be used assuppositories. The two main types of capsules are hard-shelled capsules,which are normally used for dry, powdered ingredients, and soft-shelledcapsules, primarily used for oils and for active ingredients that aredissolved or suspended in oil. Both of these classes of capsule are madeboth from gelatine and from plant-based gelling substances likecarrageenans and modified forms of starch and cellulose.

Since their inception, capsules have been viewed as the medium of morepotent medicines than tablets, which are more commonly associated withweaker over-the-counter drugs.

A tablet is usually a compressed preparation that contains, 5-10% of thedrug (active substance); 80% of fillers, disintegrants, lubricants,glidants, and binders; and 10% of compounds which ensure easydisintegration, disaggregation, and dissolution of the tablet in thestomach or the intestine.

The disintegration time can be modified for a rapid effect or forsustained release. Special coatings can make the tablet resistant to thestomach acids such that it only disintegrates in the duodenum as aresult of enzyme action or alkaline pH.

Pills can be coated with sugar, varnish, or wax to diguise the taste.Some tablets are designed with an osmotically active core, surrounded byan impermeable membrane with a pore in it. This allows the drug topercolate out from the tablet at a constant rate as the tablet movesthrough the digestive tract.

An injection is a method of putting liquid into the body with a hollowneedle and a syringe which is pierced through the skin long enough forthe material to be forced into the body.

An emulsion is a mixture of two immiscible (unblendable) substances. Onesubstance (the dispersed phase) is dispersed in the other (thecontinuous phase). Examples of emulsions include propofol, among others.

Emulsions tend to have a cloudy appearance, because the many phaseinterfaces scatter light that passes through the emulsion. Emulsions areunstable and thus do not form spontaneously. Energy input throughshaking, stirring, homogenizers, or spray processes are needed to forman emulsion. Over time, emulsions tend to revert to the stable state ofoil separated from water. Surface active substances can increase thekinetic stability of emulsions greatly so that, once formed, theemulsion does not change significantly over years of storage. Thisphenomenon is called coalescence, and happens when small dropletsrecombine to form bigger ones. Fluid emulsions can also suffer fromcreaming, the migration of one of the substances to the top of theemulsion.

Other types of non-limiting dosage forms within the scope of the presentinvention are set forth in Table I.

In one embodiment, the nanomaterials of the invention are fabricatedinto a pharmaceutical dosage form whereby the nanomaterials are used tomonitor quality parameters of the drug product enclosed therein.

In a further embodiment, the nanomaterials of the invention arefabricated into a pharmaceutical dosage form set forth in Table Iwhereby the nanomaterials are used to monitor quality parameters of thedrug product enclosed therein.

In a preferred embodiment, the nanomaterials disclosed herein arefabricated into a pharmaceutical dosage form set forth in Table Iwhereby the dosage form comprise the nanomaterial or are fabricated toconsist of 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%,15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%,29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%,43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%,57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%,71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%,85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or99% nanomaterial and the remaining ingredients of the specified dosageform are known in the art.

VI.) Routes of Administration

A route of administration is the path by which a drug, fluid, or othersubstance is brought into contact with the body.

As one of ordinary skill in the art will appreciate, a substance must betransported from the site of entry to the part of the body where itsaction is desired to take place. However, using the body's transportmechanisms for this purpose can be far from trivial. The pharmacokineticproperties of a drug are critically influenced by the route ofadministration.

Routes of administration can broadly be divided into three categories.Topical, wherein a local effect is desired. A substance is applieddirectly where its action is desired. Enteral, wherein the desiredeffect is systemic (non-local). An example is a substance is given viathe digestive tract. Parenteral, wherein the desired effect is systemic.A substance is given by other routes than the digestive tract (i.e.injection). Table II summarizes the general routes of administration.

VII.) Supply Chain Management

Proper supply chain management of packaged pharmaceuticals is criticalto provide quality drugs to end-users. This includes monitoringtraditional areas of supply chain to include packaging, productprotection, storage, and distribution. In addition, monitoring the ColdChain (i.e. a subset of the supply chain that require temperaturecontrol) in order to retain drugs key properties is vital. Specifically,from the point when the drug product is packaged until it reaches theend-user (See, FIG. 6). Depending on the geographic location of theend-user and circumstances surrounding the need for treatment (i.e. anatural disaster), this could take weeks, months, etc.

Additionally, not all cold chain products are the same and the need formonitoring temperature and other quality parameters differs for eachtype of drug product. Table III sets forth the generally recognizedcategories of temperatures in cold chain compliance. In addition, TableIV shows general consequences of what happens to drug products when coldchain management fails.

In one embodiment, the invention provides for a method of monitoringquality of a drug product whereby the dosage form comprises ananomaterial fabricated into the dosage form and whereby thenanomaterial monitors the quality parameters set for the quality controlunit.

In a further embodiment, the invention provides for a method ofmonitoring quality of a drug product whereby the dosage form comprises ananomaterial fabricated into the dosage form and whereby the monitoringoccurs from packaging to distribution (See, FIG. 6).

In a further embodiment, the invention provides for a method ofmonitoring quality of a drug product whereby the dosage form comprises ananomaterial fabricated into the dosage form and whereby the monitoringoccurs from distribution to wholesale (See, FIG. 6).

In a further embodiment, the invention provides for a method ofmonitoring quality of a drug product whereby the dosage form comprises ananomaterial fabricated into the dosage form and whereby the monitoringoccurs from wholesale to retail (See, FIG. 6).

In a further embodiment, the invention provides for a method ofmonitoring quality of a drug product whereby the dosage form comprises ananomaterial fabricated into the dosage form and whereby the monitoringoccurs from retail to the end user (See, FIG. 6).

In a preferred embodiment, the invention provides for a method ofmonitoring quality of a drug product in a cold chain whereby the dosageform comprises a nanomaterial fabricated into the dosage form andwhereby the temperature monitoring occurs from packaging to the end user(See, FIG. 6).

VII.) Kits/Articles of Manufacture

For use in monitoring quality of drug products enclosed withinpharmaceutical dosage forms (Table I) described herein, kits are withinthe scope of the invention. Such kits can comprise a carrier, package,or container that is compartmentalized to receive one or more containerssuch as boxes, shrink wrap, and the like, each of the container(s)comprising one of the separate elements to be used in the method, alongwith a program or insert comprising instructions for use, such as a usedescribed herein.

The kit of the invention will typically comprise the container describedabove and one or more other containers associated therewith thatcomprise nanomaterials fabricated into pharmaceutical dosage formsdesirable from a commercial and user standpoint, listing contents and/orinstructions for use, and package inserts with instructions for use.

A program can be present on or with the container. Directions and orother information can also be included on an insert(s) or program(s)which is included with or on the kit. The program can be on orassociated with the container.

The terms “kit” and “article of manufacture” can be used as synonyms.

The article of manufacture typically comprises at least one containerand at least one program. The containers can be formed from a variety ofmaterials such as glass, metal or plastic.

EXAMPLES

Various aspects of the invention are further described and illustratedby way of the several examples that follow, none of which is intended tolimit the scope of the invention.

Example 1 Thermally Conductive Nanomaterials Fabricated into Pre-FilledSyringes

The nanomaterial with enhanced thermal conductivity is generated bymethods known in the art. The nanomaterial is formed into sheetsproviding an interface between the thermal pad and the drug product andproviding an interface between the thermal pad and a thermal biosensor.(FIG. 1). In one embodiment, the nanomaterial is fabricated into apre-filled syringe. The thermal biosensor monitors temperature of thedrug product enclosed therein (e.g. a vaccine). When the temperaturefalls outside the pre-set parameter(s) a schema notifies the end-user(e.g. doctor, patient, nurse, etc.) and the dosage form is discarded orcorrective action is taken. (FIG. 2).

In one embodiment, the monitoring and quality assessment achieves a stepof supply chain management whereby drug product quality and shelf-lifeare increased. Costs are reduced over time.

In a further embodiment, the monitoring and quality assessment achievesa step of cold chain management whereby drug product quality andshelf-life are increased. Costs are reduced over time.

Example 2 Quality Monitoring of Drug Product Using Nanomaterials withEnhanced Luminescent Properties

The nanomaterial with enhanced luminescent properties is generated bymethods known in the art. Dosage forms fabricated with the nanomaterialsare produced by standard methods and a drug product is enclosed therein.Sensors monitor such properties as pH, temperature, degradation,potency, solubility, and other properties affecting drug productefficacy. When the pre-set property falls outside the qualityparameter(s) a schema notifies the end-user (e.g. doctor, patient,nurse, etc.) and the dosage form is discarded or corrective action istaken. In one embodiment, the schema comprises a color change in thedosage form. In one embodiment, the schema comprises a symbol display onthe dosage form. In one embodiment, the schema comprises a word displayon the dosage form. (FIG. 3).

Example 3 Optically Enhanced Nanomaterials Fabricated into Dosage FormsEnclosing Emulsions

The nanomaterial with enhanced optical properties is generated bymethods known in the art. The nanomaterial is formed into graded indexlens whereby the thickness of the lens is uniform providing an optimalinterface between the contact lens the dosage form and the opticalfiber. (FIG. 4). In one embodiment, the nanomaterial is fabricated intoa dosage form enclosing an emulsion.

An emulsion is a mixture of two or more immiscible (unblendable)substances. One substance (the dispersed phase) is dispersed in theother (the continuous phase).

Emulsions tend to have a cloudy appearance, because the many phaseinterfaces scatter light that passes through the emulsion. Emulsions areunstable and thus do not form spontaneously. Energy input throughshaking, stirring, homogenizers, or spray processes are needed to forman emulsion. Over time, emulsions tend to revert to a stable state.Additionally, surface active substances can increase the kineticstability of emulsions greatly so that, once formed, the emulsion doesnot change significantly over years of storage.

However, some emulsions are so unstable that they will quickly separateunless continuous energy is applied. Fluid emulsions can also sufferfrom creaming, the migration of one of the substances to the top of theemulsion under the influence of buoyancy.

Emulsions are part of a more general class of two-phase systems ofmatter called colloids. Although the terms colloid and emulsion aresometimes used interchangeably, emulsion tends to imply that both thedispersed and the continuous phase are liquid.

There are three types of emulsion instability, (i) flocculation, wherethe particles form clumps; (ii) creaming, where the particlesconcentrate towards the surface (or bottom, depending on the relativedensity of the two phases) of the mixture while staying separated; and(iii) breaking and coalescence where the particles coalesce and form alayer of liquid.

Accordingly, the contact lens monitors phase transformation of theemulsion enclosed within the dosage form. When the phase transitionfalls outside the pre-set parameter(s) the end-user (e.g. doctor,patient, nurse, etc.) provides a visual inspection and the dosage formis discarded or corrective action is taken. (FIG. 5).

In one embodiment, the monitoring and quality assessment achieves a stepof supply chain management whereby drug product quality and shelf-lifeare increased. Costs are reduced over time.

In a further embodiment, the monitoring and quality assessment achievesa step of cold chain management whereby drug product quality andshelf-life are increased. Costs are reduced over time.

Example 4 Methods of Monitoring Quality of Drug Product Using DosageForms Fabricated with Nanomaterials

The final formulation of the drug product is determined and is packagedusing standards methods known in the art into dosage forms fabricatedwith nanomaterials. The dosage forms comprise a detection schema tonotify end-users (doctors, patients, hospitals, etc.) when the drugproduct properties being monitored fall outside the quality protocol.

In one embodiment, the invention provides for a method of monitoringquality of a drug product whereby the dosage form comprises ananomaterial fabricated into the dosage form and whereby thenanomaterial monitors the quality parameters set for the quality controlunit.

In a further embodiment, the invention provides for a method ofmonitoring quality of a drug product whereby the dosage form comprises ananomaterial fabricated into the dosage form and whereby the monitoringoccurs from packaging to distribution (See, FIG. 6).

In a further embodiment, the invention provides for a method ofmonitoring quality of a drug product whereby the dosage form comprises ananomaterial fabricated into the dosage form and whereby the monitoringoccurs from distribution to wholesale (See, FIG. 6).

In a further embodiment, the invention provides for a method ofmonitoring quality of a drug product whereby the dosage form comprises ananomaterial fabricated into the dosage form and whereby the monitoringoccurs from wholesale to retail (See, FIG. 6).

In a further embodiment, the invention provides for a method ofmonitoring qualify of a drug product whereby the dosage form comprises ananomaterial fabricated into the dosage form and whereby the monitoringoccurs from retail to the end user (See, FIG. 6).

In a preferred embodiment, the invention provides for a method ofmonitoring quality of a drug product in a cold chain whereby the dosageform comprises a nanomaterial fabricated into the dosage form andwhereby the temperature monitoring occurs from packaging to the end user(See, FIG. 6). Table III shows generally recognized temperatures in coldchain compliance.

In one embodiment, the monitoring achieves a step of supply chainmanagement whereby drug product quality and shelf-life are increased.Costs are streamlined over time.

The present invention is not to be limited in scope by the embodimentsdisclosed herein, which are intended as single illustrations ofindividual aspects of the invention, and any that are functionallyequivalent are within the scope of the invention. Various modificationsto the models and methods of the invention, in addition to thosedescribed herein, will become apparent to those skilled in the art fromthe foregoing description and teachings, and are similarly intended tofall within the scope of the invention. Such modifications or otherembodiments can be practiced without departing from the true scope andspirit of the invention.

TABLE I Types of Dosage Forms Types of generally recognized Dosage FormsAEROSOL AEROSOL, FOAM AEROSOL, METERED AEROSOL, POWDER AEROSOL, SPRAYBAR, CHEWABLE BEAD BEAD, IMPLANT, EXTENDED RELEASE BLOCK CAPSULECAPSULE, COATED CAPSULE, COATED PELLETS CAPSULE, COATED, EXTENDEDRELEASE CAPSULE, DELAYED RELEASE CAPSULE, DELAYED RELEASE PELLETSCAPSULE, EXTENDED RELEASE CAPSULE, FILM COATED, EXTENDED RELEASECAPSULE, GELATIN COATED CAPSULE, LIQUID FILLED CEMENT CIGARETTE CONECORE, EXTENDED RELEASE CREAM CRYSTAL CULTURE DENTIFRICE DENTIFRICE/GELDIAPHRAGM DISC DOUCHE DRESSING ELIXIR EMULSION ENEMA EXTRACT FILM FILM,EXTENDED RELEASE FILM, SOLUBLE GAS GEL GEL, JELLY GENERATOR GLOBULEGRAFT GRANULE GRANULE, DELAYED RELEASE GRANULE, EFFERVESCENT GRANULE,FOR SOLUTION GRANULE, FOR SUSPENSION GRANULE, FOR SUSPENSION, EXTENDEDRELEASE GUM GUM, CHEWING GUM, RESIN INHALANT INJECTION INJECTION,EMULSION INJECTION, POWDER, FOR SOLUTION INJECTION, POWDER, FORSUSPENSION INJECTION, POWDER, FOR SUSPENSION, EXTENDED RELEASEINJECTION, POWDER, LYOPHILIZED, FOR LIPOSOMAL SUSPENSION INJECTION,POWDER, LYOPHILIZED, FOR SOLUTION INJECTION, POWDER, LYOPHILIZED, FORSUSPENSION INJECTION, POWDER, LYOPHILIZED, FOR SUSPENSION, EXTENDEDRELEASE INJECTION, SOLUTION INJECTION, SOLUTION, CONCENTRATE INJECTION,SUSPENSION INJECTION, SUSPENSION, EXTENDED RELEASE INJECTION,SUSPENSION, LIPOSOMAL INSERT, EXTENDED RELEASE INTRAUTERINE DEVICEIRRIGANT LINIMENT LIPSTICK LIQUID LOLLIPOP LOTION LOZENGE MOUTHWASH OILOINTMENT PASTE PASTE, DENTIFRICE PATCH, EXTENDED RELEASE PATCH, EXTENDEDRELEASE, ELECTRICALLY CONTROLLED PELLET PILL POWDER POWDER, DENTIFRICEPOWDER, FOR SOLUTION POWDER, FOR SUSPENSION RINSE SALVE SHAMPOO SHAMPOO,SUSPENSION SOAP SOLUTION SOLUTION, CONCENTRATE SOLUTION, FOR SLUSHSPONGE SPRAY SPRAY, METERED SPRAY, METERED PUMP SPRAY, SUSPENSION STICKSTRIP SUPPOSITORY SUPPOSITORY, EXTENDED RELEASE SUSPENSION SUSPENSION,EXTENDED RELEASE SYRUP TABLET TABLET, CHEWABLE TABLET, COATED TABLET,DELAYED RELEASE TABLET, DELAYED RELEASE PARTICLES TABLET, EFFERVESCENTTABLET, EXTENDED RELEASE TABLET, FILM COATED TABLET, FILM COATED,EXTENDED RELEASE TABLET, MULTILAYER TABLET, MULTILAYER, EXTENDED RELEASETABLET, SOLUBLE TABLET, SUGAR COATED WAFER

TABLE II Generally known Routes of Administration Topical epicutaneous(application onto the skin) inhalational enema eye drops (onto theconjunctiva) ear drops intranasal (into the nose) vaginal Enternal bymouth (orally) by gastric feeding tube rectally Parenteral intravenous(into a vein) intraarterial (into an artery) intramuscular (into amuscle) intracardiac (into the heart) subcutaneous (under the skin)intraosseous infusion (into the bone marrow) intradermal, (into the skinitself) intrathecal (into the spinal canal) intraperitoneal, (infusionor injection into the peritoneum) is predominantly used in veterinarymedicine and animal testing transdermal (diffusion through the intactskin) transmucosal (diffusion through a mucous membrane) inhalationalOther epidural intravitreal

TABLE III Generally recognized tempuratures in cold chain complianceTemperature Range (stated in C° Category and F°) Frozen −25° and −10° C.(−13° and 14° F.) Cold Any temperature not exceeding 8° C. (46° F.) CoolBetween 8° and 15° C. (46° and 59° F.) Temperature Controlled Thermostatcontrolled of 20° to 25° C. (68° to 77° F.) Room Temperature Temperatureprevailing in area (no thermostat) Warm Between 30° and 40° C. (86° to104° F.) Excessive Heat Above 40° C. (104° F.)

TABLE IV Common Results of variations of temperature outside definedrange Results when drug products recommended to be stored at 15°-25° C.are exposed to temperatures above 30° C. Physical Changes ChemicalChanges Separation of emulsion systems Increased rate of degradationSedimentation of active ingredients Increased rate of toxic degradationLoss of “volatile” components and Increased rate of interactionflavoring agents with direct contact of packaging material Changes incrystalline structure of fatty Increased interactions of bases andactive ingredients components in aqueous solution

1) A method of fabricating a nanomaterial into a pharmaceutical dosageform said method comprising, a) contacting a nanomaterial to apharmaceutical dosage form; b) interfacing the nanomaterial with a drugproduct enclosed within the pharmaceutical dosage form. c) enclosing thedrug product into the pharmaceutical dosage form whereby thenanomaterial monitors the drug product properties. 2) The method claim1, wherein the nanomaterial is selected from the group consisting of ananopowder, nanowire, nanofiller, nanocrystal, and nanocomposite. 3) Themethod of claim 1, wherein the pharmaceutical dosage form is set forthin Table I. 4) The method of claim 1, wherein the drug productproperties are selected from the group consisting of pH, temperature,oxidation, degradation, potency, and leachates. 5) A kit comprising thepharmaceutical dosage form of claim
 1. 6) A method of monitoring qualityof a drug product enclosed within a pharmaceutical dosage form saidmethod comprising, a) Enclosing a drug product in a pharmaceuticaldosage form fabricated with a nanomaterial; b) monitoring properties ofthe drug product enclosed therein with the nanomaterial; c) analyzing aquality schema to make a risk based assessment; 7) The method of claim6, wherein the monitoring occurs from the point of packaging until thedrug product reaches the end user. 8) The method of claim 6, wherein theproperties are selected from the group consisting of pH, temperature,phase transition, degradation, potency, and solubility. 9) The method ofclaim 6, wherein the quality schema is selected from the groupconsisting of color change, symbol display, and word display. 10) Themethod of claim 6, wherein the nanomaterial is optically enhanced. 11)The method of claim 6, wherein the nanomaterial is thermally enhanced.12) The method of claim 6, wherein the monitoring occurs in a coldchain. 13) A kit comprising a pharmaceutical dosage form which performsthe method of claim
 6. 14) A pharmaceutical dosage form by a processcomprising, a) fabricating a pharmaceutical dosage form with afunctional nanomaterial; b) operably interfacing the functionalnanomaterial with a drug product enclosed within the dosage form; c)enclosing the drug product into the pharmaceutical dosage form whereinthe pharmaceutical dosage form monitors the quality of the drug product.15) The dosage form of claim 14, wherein said dosage form is selectedfrom Table I.